Shock is a complex entity, which traditionally has been defined as a state in which the metabolic demands of tissues are not matched by sufficient delivery of metabolic substrates, with the major substrate being oxygen. This mismatch commonly results from altered states of organ perfusion such as hemorrhage. Shock additionally involves complex inflammatory and immune mediated events which result from, and may further exacerbate, this initial metabolic mismatch. Many of these events play an important role in the development of subsequent multiorgan dysfunction, failure and death, with this latter mode responsible for over 60% of trauma deaths. Haljamae, H., “Cellular metabolic consequences of altered perfusion,” in Gutierres, G., Vincent, J., eds., “Update in Intensive Care and Emergency Medicine: Tissue oxygen utilization (Springer Verlag, 1991), pp. 71–86. Despite the complexities of the inflammatory and immune components of trauma and hemorrhage, there is little debate on linking the severity of these events to the severity of initial perfusion deficits and tissue hypoxia. It is therefore essential to recognize and correct perfusion deficits at their earliest possible time. Although this seems intuitive, up to 80% of trauma patients on close monitoring continue to demonstrate evidence of tissue hypoxia secondary to perfusion deficits after what was considered to be complete resuscitation. Abou-Khalil, B., Scalea, T. M., Trooskin, S. Z., Henry, S. M., Hitchcock, R., “Hemodynamic responses to shock in young trauma patients; need for invasive monitoring,” Crit. Care Med., 22:633–639 (1994).
Traditional clinical signs of tissue perfusion such as capillary refill, mental status, heart rate, pulse pressure and systemic blood pressure are very gross indicators of tissue perfusion and can only be considered to be of historic interest except at extreme values. Porter, J., Ivatury, R., “In search of optimal end points of resuscitation in trauma patients,” J. Trauma, 44:908–914 (1998). Current markers of tissue perfusion include systemic lactate and base deficit measurements; transcutaneous and subcutaneous gas measurements, gastric and sublingual tonometry and spectroscopic techniques such as NIR absorption spectroscopy, fluorescence quenching, and orthogonal polarization spectral imaging. While these techniques have respective advantages, each is plagued by the relative singularity of its measure, lack of tissue specificity, inability to quantitate, or inability to easily apply or adapt for field use. Identification of any other useful markers is an important objective, and the search continues for further markers of shock states and the like. Effectively measuring and working with both known markers as well as markers being discovered would be highly beneficial to emergency medicine but is not provided in conventional technology. Information about biochemistry in shock states and disease states has not yet fully found its way and been used in practical applications. Rather, currently emergency medicine is left to rely on physical examination not much advanced by conventional, relatively limited spectroscopic measurement technology.
That is, much still turns on observation of simple vital signs. Yet, the diagnosis of shock and its severity can be difficult, and cannot be accomplished with certainty, from simple vital signs. A physical exam, including vital signs, is inadequate in detecting states of uncompensated shock. Ward, K. R., Ivatury, R. R., Barbee, R. W., “Endpoints of resuscitation for the victim of trauma,” J. Intensive Care Med., 16:55–75 (2001). Dysoxia can be present despite normal vital signs. Ward et al., id.; Abou-Khalil, B., Scalea, T. M., Trooskin, S. Z., Henry, S. M., Hitchock, R., “Hemodynamic response to shock in young trauma patients: need for invasive monitoring,” Crit Care Med. 22(4):633–9 (1994); Scalea, T. M., Maltz, S., Yelon, J., Trooskin, S. Z., Duncan, A. O, Scalafani, S. J., “Resuscitation of multiple trauma and head injury: role of crystalloid fluids and inotropes,” Crit Care Med. 22(10):1610–5 (1994); Ivatury, R. R., Simon, R. J., Havriliak, D., Garcia, C., Greebarg, J., Stahl, W. M., “Gastric mucosal pH and oxygen delivery and oxygen consumption indices in the assessment of adequacy of resuscitation after trauma: a prospsective, randomized study,” J. Trauma, 39(1):128–34; discussion 34–6 (1995).
In addition, resuscitation of victims of uncompensated shock back to “normal” vital signs is inadequate as a resuscitation endpoint. Unrecognized continued accumulation of additional oxygen debt is still possible and may contribute to later development of multisystem organ failure and death. Shoemaker, W. C., Appel, P. L., Kram, H. B., “Tissue oxygen debt as a determinant of lethal and nonlethal postoperative organ failure,” Crit. Care Med., 16(11):1117–20 (1988).
Adding, to a physical exam, global measures of oxygen transport still does not ensure detection of early shock states or provide adequate information to act as sole end-points of resuscitation once shock is recognized and therapy instituted. For an outline of all of the current major technologies that have been used to detect the presence of shock and to guide its treatment, see Ward, Ivatury et al., supra. For various reasons, all have been problematic.
To better understand the difficulties in detecting shock states it is helpful to examine the biphasic relationship between oxygen delivery (DO2) and consumption (VO2) to understand the potential inadequacies of currently available monitoring systems. FIG. 1 demonstrates that VO2 can remain constant over a wide range of DO2. This is possible because cells have the ability to increase their extraction of oxygen (OER) in the face of decreased delivery. This is generally reflected by lower hemoglobin oxygen saturations in blood leaving the organ system (SvO2), which may change before it is apparent in the physical exam. Scalea, T. M., Hartnett, R. W., Duncan, A. O., Atrweh, N. A., Phillips, T. F., Sclafani, S. J., et al., “Central venous oxygen saturation: a useful clinical tool in trauma patients,” J. Trauma, 30(12):1539–43 (1990); McKinley, B. A., Marvin R. G., Cocanour, C. S., Moore, F. A., “Tissue hemoglobin O2 saturation during resuscitation of traumatic shock monitored using near infrared spectrometry,” J. Trauma, 48(4):637–42 (2000). However, there is a point at which OER cannot keep pace with reductions in delivery. At this point VO2 of the cell or organ falls (critical oxygen delivery: DO2crit) and cells become dysoxic. This results in an increase in the oxidation-reduction (redox) value of the cell, effectively blocking the flow of electrons through the NADH-cytochrome a, a3 cascade in the mitochondria which prevents the formation of ATP. Cytochrome a,a3 (cytochrome oxidase) is the terminal electron acceptor in the mitochondrial electron transport chain. Dysoxia can be recognized by the accumulation of a number of metabolic products such as lactate and intracellular reduced nicotinamide adenine dinucleotide (NADH). NADH offers one of the main sources of energy transfer from the TCA cycle to the respiratory chain in the mitochondria. NADH is situated on the high-energy site of the respiratory chain and during tissue dysoxia it accumulates because less NADH is oxidized to NAD+. The redox state of the mitochondria (NADH/NAD+) therefore reflects the mitochondrial energy state, which in turn is determined by the balance of oxygen availability in the cell and the metabolic rate of the cell. Siegemund, M., van Bommel, J., Ince, C., “Assessment of regional tissue oxygenation,” Intensive Care Med., 25(10):1044–60 (1999). Conventional monitoring and measuring used in emergency medicine do not adequately take into account such biochemistry of shock states and the like. Knowing the biochemistry of shock states and the like but not being able to measure and monitor pertinent information thereto has been a frustrating, unresolved problem in emergency medicine.
Conventionally, a primary means of assessing tissue perfusion is through infrared (IR) or near-infrared (NIR) spectroscopy. Human skin and tissue are semi-transparent to wavelengths in this range. However, problems with IR technology arise because water strongly absorbs IR radiation. While NIR absorption spectroscopy does not suffer from water absorption as does classical IR, and NIR absorption spectroscopy is useful for the relative quantification of several specific chromophores such as hemoglobin, myoglobin, and cytochrome oxidase. Nakamoto, K., Czernuszewicz, W. S., “Infrared Spectroscopy,” in: Methods in Enzymology, 226:259–289 (1993); Piantadisu, C., Parsons, W., Griebel, “Application of NIR Spectroscopy to problems of tissue oxygenation,” in Gutierres, G., Vincent, J., eds., Update in Intensive Care and Emergency Medicine: Tissue oxygen utilization (Springer Verlag, 1991) pp. 41–44. Other recent work reports the ability of using NIR absorption shift of hemoglobin to measure pH. However, disadvantageously, NIR signals are so broad as to not be well-suited to quantification of overlapping species. Examples of NIR absorption spectroscopy signals being too broad to lend themselves to quantification of overlapping species include the spectra for oxy and deoxy hemoglobin and cytochrome oxidase (see FIG. 2). Owen-Reece, H., Smith, M., Elwell, C. E., Goldstone, J. C., “Near infrared spectroscopy,” Br J Anaesth, 82(3): 418–26 (1999). FIG. 2 is a graph of typical broad signals of oxy and deoxy hemoglobin and cytochrome oxidase obtained by NIR absorption spectroscopy. (In FIG. 2, the HbO2 and Hb signals also would include those from myoglobin.)
Conventional NADH-fluorescence techniques are more specific and quantitative than classical NIR absorption spectra but can only measure a single marker. The technique has relied on use of excitation wavelengths in the carcinogenic UV region and has not been reduced to clinical practice. Conventional noninvasive or minimally invasive measures of tissue perfusion include transcutaneous and tonometric (gastric or sublingual) monitoring of various gases such as oxygen and carbon dioxide. The major limitations of these devices are that they are limited to monitoring those specific gases and cannot provide additional information that, if provided, could be useful in diagnosis and stratification of patients. Methods such as tonometry can be cumbersome due to its invasive nature. These methods are also prone to deviations through changes either in minute ventilation or inspired oxygen concentration. Transcutaneous gas monitoring, gastric tonometry, and even sublingual tonometry are one-dimensional and are prone to non-flow related changes caused by hypo or hyper ventilation. Also, with the exception of sublingual tonometry, application of these methods in the field is problematic. Weil, M., Nakagawa, Y., Tang, W., et al., “Sublingual capnometry: A new noninvasive measurement for diagnosis and quantification of severity of circulatory shock,” Crit. Care Med., 27:1225–1229 (1999).
Another concern associated with measurement of shock states, and balanced with other factors relating to measurement, is invasiveness. NIR absorption spectroscopy is being aggressively studied to use signals from these chromophores to noninvasively monitor oxygen transport at the tissue level. McKinley et al., supra. Perhaps the best-known use of this technology is in the monitoring of cerebral hemodynamics. The basis for this is that the majority of blood volume in an organ is venous and thus the tissue hemoglobin saturation should reflect the state of oxygen consumption of the tissue. Again, broad overlap of signals in addition to needing to know the pathlength of light presents challenges in quantification and differentiation of signals. For example it is difficult to distinguish hemoglobin and myoglobin making NIR use in hemorrhage problematic since myoglobin has a p50 of only 5 mmHg. Gayeski, T. E., Honig, C. R., “Direct measurement of intracellular O2 gradients; role of convection and myoglobin,” Adv Exp Med Biol, 159:613–21 (1983). Because soft tissue and bone are translucent to NIR light, NIR can penetrate to significant depths, a feature with both advantages and disadvantages. Monitoring the redox state of cytochrome oxidase is also difficult unless baseline absorptions are known. There is also significant overlap between the cytochrome oxidase and hemoglobin signals. Despite this, NIR measurements of tissue saturation (StO2) are being marketed.
Although some manufacturers of NIR absorption spectroscopy equipment claim to differentiate between the two species of oxygen hemoglobin and myoglobin, no work to this effect exists in the medical literature. In fact, evidence exists that a major portion of the NIR absorption spectroscopy signal reported from hemoglobin actually originates from myoglobin.
Another problem for NIR is that in terms of use on hollow organ systems such as the stomach, data from NIR absorption spectroscopy would likely include signals from non-stomach organs and thus not reflect data from the mucosal surface of the stomach.
Surface NADH fluorescence has been used to detect cellular dysoxia in a number of organ systems. Siegemund et al., supra. The traditional technique uses unique excitation light sources and detection filters to take advantage of the fact that NADH will fluoresce (emit light at 460 nm) when excited at a wavelength of 360 nm (near-UV). This technique has been used in video microscopy/fluorometry experiments. Van der Laan, L., Coremans, A., Ince, C., Bruining, H. A., “NADH videofluorimetry to monitor the energy state of skeletal muscle in vivo,” J. Surg. Res., 74(2):155–60 (1998). However, such conventional methods do not necessarily provide optimum resolution.
Adverse effects of certain compounds (such as vasopressin and norepinephrine) on oxygen transport and the immune/inflammatory response are now beginning to be appreciated with manipulation of their actions being studied as therapeutic strategies. Kincaid, E. H., Miller, P. R., Meredith, J. W., Chang, M. C., “Enalaprilat improves gut perfusion in critically injured patients,” Shock, 9(2):79–83 (1998); Catania, R. A., Chaudry, I. H., “Immunological consequences of trauma and shock,” Ann. Acad. Med. Singapore, 28(1):120–32 (1999). However, satisfactory measurement of such compounds in vivo without invasive probing has not yet been provided.
Thus, current technology includes pulmonary artery catheters, repetitive measures of lactate and base deficit, splanchnic tonometry, sublingual tonometry, NIR absorption spectroscopy, transcutaneous gas monitoring, phosphorescence quenching and fluorescence technology (indwelling blood gas/pH catheters). No such technology is without a substantial disadvantage. Civilian prehospital emergency medical services systems, emergency physicians, trauma surgeons, intensive care physicians, cardiologists, anethesiologists, and military medical personnel continue to be plagued by the insensitivity of the physical exam, lack of readily available physiologic and metabolic markers to judge the presence and severity of shock states, and lack of real-time relevant measurement approaches. In addition, it has been difficult to use singular measures to guide treatment or predict outcome. These problems are greatly magnified as the scale of the wounded population increases (such as on the battlefield and the various pre-definitive echelons of care provided to wounded soldiers or in a natural disaster). To the inventors' knowledge, currently no conventional techniques are available for real-time monitoring of a broad range of potentially valuable emergency medicine markers of shock, tissue ischemia, tissue injury, tissue inflammation, or tissue immune dysfunction.